TABLE 3.
Selection of resistant variants in NS5A by ombitasvir in genotype 2 to 6 subgenomic chimeric replicon cell lines
| Genotype | Variant | Prevalence in replicon assaysa | Mean EC50 (pM) ± SDb | Fold resistance |
|---|---|---|---|---|
| 2ac | Wild type | 1.3 ± 0.1 | ||
| T24A | 8/15 | 50 ± 6.9 | 38 | |
| T24A (L31) | 20 ± 0.37 | 15 | ||
| F28S | 4/15 | 4,710d | ||
| 2bc | Wild type | 0.71 ± 0.37 | ||
| L28F | 1/24 | 33 ± 6.1 | 47 | |
| L28F (M31) | 176 ± 30 | 247 | ||
| L31V | 8/24 | 361 ± 70 | 511 | |
| Y93H | 13/24 | NA | ||
| 3a | wt | 4.4 ± 2.4 | ||
| M28T | 3/24 | 2,934 ± 1,618 | 659 | |
| L31F | 3/24 | 28d | ||
| Y93H | 14/24 | 29,940 ± 368 | 6,728 | |
| 4a | Wild type | 0.35 ± 0.07 | ||
| L28V | 21/21 | 8.0 ± 2.8 | 23 | |
| 5a | Wild type | 0.91 ± 0.34 | ||
| L28I | 6/23 | 72 ± 25 | 79 | |
| L31V | 12/23 | 220 ± 105 | 243 | |
| L31F | 6/23 | 263 ± 117 | 289 | |
| 6a | Wild type | 82 ± 58 | ||
| L31V | 4/24 | 5,572 ± 734 | 68 | |
| T58N | 4/24 | 8,354 ± 1,248 | 101 | |
| T58A | 8/24 | 1,452 ± 599 | 18 | |
| T58S | 6/24 | 1,504 ± 319 | 18 |
a
Number of times this variant was found/total number of colonies analyzed.
b
EC50 of ombitasvir in replicon containing the variant in NS5A determined using transient luciferase assay. NA, not available due to low replication efficiency of the variant.
c
The genotype 2a replicon cell line contains Met at position 31; the genotype 2b replicon cell line contains Leu at position 31.
d
F28S in GT 2a and L31F in GT 3a replicated poorly in a transient assay; therefore, the EC50 and fold resistance were evaluated in a stable chimeric replicon cell line.